Hydroxychloroquine-induced cardiomyopathy: role of cardiac magnetic resonance for the diagnosis and follow-up of a very rare entity—a case report

Abstract Background Hydroxychloroquine (HCQ) is a disease-modifying antirheumatic used in rheumatological diseases such as systemic lupus erythematosus. Long-term exposure to HCQ results in drug accumulation and predisposes to adverse effects. Case summary We present the case of a 45-year-old woman with long-term treatment with HCQ who presented to the Emergency Department with acute heart failure. Transthoracic echocardiogram, previously normal, showed severe biventricular hypertrophy and biventricular systolic dysfunction. Cardiac magnetic resonance (CMR) confirmed the previous findings and showed elevated native T1 and T2 values, elevated extracellular volume, and extensive mid-wall late gadolinium enhancement (LGE). Infiltrative cardiomyopathy was suspected, and endomyocardial biopsy performed. Light microscopy showed myocyte hypertrophy and vacuolar change and absence of lymphocytic inflammatory infiltrates. The diagnosis of HCQ-induced cardiomyopathy was established, and the drug was withdrawn. A CMR performed 1 year later showed normal systolic function of both ventricles and normalization of T2 values, reflecting resolution of myocardial oedema. However, severe hypertrophy, elevated native T1 values, and LGE persisted. Discussion Our case shows that although discontinuation of the drug stops the progression of the disease, established myocardial structural damage persists. Early diagnosis of this entity is therefore essential to improve prognosis.


Background
Hydroxychloroquine (HCQ) is a disease-modifying antirheumatic used in rheumatological diseases such as systemic lupus erythematosus.Long-term exposure to HCQ results in drug accumulation and predisposes to adverse effects.

Case summary
We present the case of a 45-year-old woman with long-term treatment with HCQ who presented to the Emergency Department with acute heart failure.Transthoracic echocardiogram, previously normal, showed severe biventricular hypertrophy and biventricular systolic dysfunction.Cardiac magnetic resonance (CMR) confirmed the previous findings and showed elevated native T1 and T2 values, elevated extracellular volume, and extensive mid-wall late gadolinium enhancement (LGE).Infiltrative cardiomyopathy was suspected, and endomyocardial biopsy performed.Light microscopy showed myocyte hypertrophy and vacuolar change and absence of lymphocytic inflammatory infiltrates.The diagnosis of HCQ-induced cardiomyopathy was established, and the drug was withdrawn.A CMR performed 1 year later showed normal systolic function of both ventricles and normalization of T2 values, reflecting resolution of myocardial oedema.However, severe hypertrophy, elevated native T1 values, and LGE persisted.

Discussion
Our case shows that although discontinuation of the drug stops the progression of the disease, established myocardial structural damage persists.Early diagnosis of this entity is therefore essential to improve prognosis.

Case presentation
As CMR findings were suggestive of myocardial inflammation but did not allow differentiation between lupus myocarditis and HCQ myocardial injury, an endomyocardial biopsy (EMB) was performed.Light microscopy showed myocyte hypertrophy with vacuolar change and no lymphocytic inflammatory infiltrates (Figure 3).The diagnosis of myocardial HCQ toxicity was therefore confirmed.An electromyogram showed mild diffuse myopathy without signs of acute inflammatory injury.The ophthalmological examination ruled out HCQ-related retinopathy.
A multidisciplinary team which included internists, cardiologists, and rheumatologists decided to discontinue HCQ and leave the remaining immunosuppressive treatment unchanged, given the absence of signs of SLE activity.The response to the decongestion strategy was good, and the dose of diuretics was progressively reduced.The patient was discharged with a rate control strategy, therefore discontinuing amiodarone.Treatment upon discharge included previous medical treatment (except HCQ and amiodarone), bisoprolol 5 mg/day, digoxin 0.25 mg/day, and torasemide 2.5 mg/day.
During follow-up, clinical evolution was good, and the patient's exercise capacity increased.A new CMR performed 1 year later showed LVEF (58%) and RVEF (49%) recovery (see Supplementary material online, Video S3) and normalization of T2 values (39 ms, ULN < 40 ms).However, biventricular hypertrophy and increased T1 (1370 ms, + 9SD) persisted.Late gadolinium enhancement imaging showed no changes compared with the previous CMR.

Discussion
Hydroxychloroquine is a disease-modifying drug used in SLE.Long-term exposure results in drug accumulation and predisposes to adverse effects. 3Cardiac effects of HCQ include conduction abnormalities, myocardial thickening, restrictive cardiomyopathy, and HF.Cardiogenic shock and cardiac arrest have been reported. 4Risk factors for AMIC include older age, female sex, pre-existing cardiac disease, and kidney disease.The duration of use and cumulative dose appear to be decisive for disease development. 3,5Extracardiac toxicity can coexist (skin changes, retinopathy, and myopathy), but cardiac events can occur in the absence of other signs of toxicity. 6Differential diagnoses of AMIC include storage disorders (Fabry disease and Pompe disease), drug-induced myopathy, mitochondrial disorders, cardiac amyloidosis, or ischaemic heart disease. 3Diagnosis of AMIC remains challenging.Cardiac magnetic resonance provides useful information, but EMB is often needed.Cardiac magnetic resonance can guide biopsy sampling.Typical CMR findings include LV or biventricular hypertrophy, systolic dysfunction, hypokinesia, and mid-wall LGE. 6In a series of patients with SLE, patients with AMIC had higher T1 and T2 compared with healthy controls and lower T1 and T2 compared with patients with myocarditis.They also found that T1 increases with longer HCQ treatment among patients with AMIC. 7he typical findings on light and electron microscopy are explained by the pathophysiology of the disease.Hydroxychloroquine enters cardiac myocytes, binds to phospholipids, and inhibits phospholipases, causing an acquired lysosomal storage disorder.This leads to glycogen and phospholipid accumulation, resulting in concentric hypertrophy. 3nder light microscopy, the most consistent finding is the vacuolization of myocytes.Electron microscopy shows myeloid bodies, curvilinear bodies, and large secondary lysosomes. 8ur patient had been treated with HCQ for 19 years and showed signs of AMIC: RBBB, LV hypokinesia, and typical findings on CMR, i.e. biventricular hypertrophy, mid-wall LGE, and elevated T1, T2, and extracellular volume.Although glycosphingolipid accumulation seems to be the initial pathophysiological insult in AMIC, which could be detected with low native T1 values, in our case, native T1 values were strikingly increased.The prolonged exposure to HCQ may have led to diffuse fibrosis and myocardial oedema, 7 indicated by increased T1 and T2 values.Indeed, the normalization of T2 12 months after withdrawal of HCQ could reflect stabilization of disease after HCQ discontinuation, similar to what is observed in AL amyloidosis when T2 values normalize after cessation of light chain deposition. 9However, though we observed biventricular systolic function recovery on follow-up CMR, hypertrophy and fibrosis persisted.
In conclusion, the diagnosis of AMIC is challenging.Although no specific sign of HCQ cardiotoxicity is available, CMR can rule out other conditions such as Fabry disease or ischaemic heart disease.Endomyocardial biopsy remains necessary in most cases to establish a definite diagnosis.Timely diagnosis is crucial to discontinue treatment with HCQ and prevent disease progression.

Lead author biography
Lucía Cobarro, MD, is a cardiologist from Madrid, Spain.She graduated from the Autonomous University of Madrid in 2018.After completing her cardiology residency at La Paz University Hospital in May 2024, she's now specializing in cardiac electrophysiology as a fellow at 12 de Octubre University Hospital.

AFigure 2
Figure 2 Mid-wall late gadolinium enhancement in the basal segments of the inferior, inferolateral, and lateral walls and mid-lateral segment of the left ventricle.Nodular enhancement foci in the apical segments of the left ventricle.Late gadolinium enhancement in the right ventricle.

Figure 1
Figure 1 Elevated mean global myocardial native T1 value, with higher values in the basal segments of the inferior, inferolateral, and lateral walls and mid-lateral segment.

Figure 3
Figure 3 Optical microscope image showing myocyte hypertrophy with vacuolar change and absence of inflammatory infiltrates in light microscopy.

- ESC curriculum 2.2 Echocardiography • 2.3 Cardiac magnetic resonance • 6.2 Heart failure with reduced ejection fraction
While retinal toxicity is one of the most feared adverse effects, HCQ can also cause cardiomyopathy.Early diagnosis of HCQ-induced cardiomyopathy, also known as antimalarial-induced cardiomyopathy (AMIC), is crucial to prevent fatal outcomes.Hydroxychloroquine-induced cardiac toxicity should be suspected if a patient on this drug develops ventricular dysfunction, prompting immediate discontinuation.Most cases reported in the literature present with a restrictive cardiomyopathy phenotype characterized by increased wall thickness, but cases of dilated cardiomyopathy have been reported.